F. De Ponti

QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience

AbstractBackground: Evidence has accrued that several non-cardiac drugs may prolong cardiac repolarisation (hence, the QT interval of the surface electrocardiogram) to such a degree that potentially life-threatening ventricular arrhythmias (e.g. torsades de pointes) may occur, especially in case of overdosage or pharmacokinetic interactions. Discussion: This has fostered discussion on the molecular mechanisms underlying the class-III anti-arrhythmic effect shared by apparently disparate classes of drugs, on the clinical relevance of this side effect and on possible guidelines to be followed by drug companies, ethics committees and regulatory agencies in the risk–benefit assessment of new and licensed drugs. This review provides an update on the different classes of non-cardiac drugs reported to prolong the QT interval (e.g. histamine H1-receptor antagonists, antipsychotics, antidepressants and macrolides), on the possible underlying molecular mechanisms and on the clinical relevance of the QT prolonging effect. Identification and widespread knowledge of risk factors that may precipitate prolongation of the QT interval into life-threatening arrhythmias becomes an important issue. Risk factors include congenital long QT syndrome, clinically significant bradycardia or heart disease, electrolyte imbalance (especially hypokalaemia, hypomagnesaemia), impaired hepatic/renal function and concomitant treatment with other drugs with known potential for pharmacokinetic/pharmacodynamic interactions (e.g. azole antifungals, macrolide antibacterials and class-I or -III anti-arrhythmic agents). Future perspectives for drug research and development are also briefly outlined.

Clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics

Antidopaminergic gastrointestinal prokinetics (bromopride, clebopride, domperidone, levosulpiride and metoclopramide) have been exploited clinically for the management of motor disorders of the upper gastrointestinal tract, including functional dyspepsia, gastric stasis of various origins and emesis. The prokinetic effect of these drugs is mediated through the blockade of enteric (neuronal and muscular) inhibitory D2 receptors. The pharmacological profiles of the marketed compounds differ in terms of their molecular structure, affinity at D2 receptors, ability to interact with other receptor systems [5‐hydroxytryptamine‐3 (5‐HT3) and 5‐HT4 receptors for metoclopramide; 5‐HT4 receptors for levosulpiride) and ability to permeate the blood–brain barrier (compared with the other compounds, domperidone does not easily cross the barrier). It has been suggested that the serotonergic (5‐HT4) component of some antidopaminergic prokinetics may enhance their therapeutic efficacy in gastrointestinal disorders, such as functional dyspepsia and diabetic gastroparesis. The antagonism of central D2 receptors may lead to both therapeutic (e.g. anti‐emetic effect due to D2 receptor blockade in the area postrema) and adverse (including hyperprolactinaemia and extrapyramidal dystonic reactions) effects. As the pituitary (as well as the area postrema) is outside the blood–brain barrier, hyperprolactinaemia is a side‐effect occurring with all antidopaminergic prokinetics, although to different extents. Extrapyramidal reactions are most commonly observed with compounds crossing the blood–brain barrier, although with some differences amongst the various agents. Prokinetics with a high dissociation constant compared with that of dopamine at the D2 receptor (i.e. compounds that bind loosely to D2 receptors in the nigrostriatal pathway) elicit fewer extrapyramidal signs and symptoms. A knowledge of central and peripheral D2 receptor pharmacology can help the clinician to choose between the antidopaminergic prokinetics to obtain a more favourable risk/benefit ratio.

Role of nitric oxide‐ and vasoactive intestinal polypeptide‐containing neurones in human gastric fundus strip relaxations

The morphological pattern and motor correlates of nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) innervation in the human isolated gastric fundus was explored. By using the nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)‐diaphorase and specific rabbit polyclonal NO‐synthase (NOS) and VIP antisera, NOS‐ and VIP‐containing varicose nerve fibres were identified throughout the muscle layer or wrapping ganglion cell bodies of the myenteric plexus. NOS‐immunoreactive (IR) neural cell bodies were more abundant than those positive for VIP‐IR. The majority of myenteric neurones containing VIP coexpressed NADPH‐diaphorase. Electrical stimulation of fundus strips caused frequency‐dependent NANC relaxations. NG‐nitro‐L‐arginine (L‐NOARG: 300 μM) enhanced the basal tone, abolished relaxations to 0.3–3 Hz (5 s) and those to 1 Hz (5 min), markedly reduced (∼50%) those elicited by 10–50 Hz, and unmasked or potentiated excitatory cholinergic responses at frequencies 1 Hz. L‐NOARG‐resistant relaxations were virtually abolished by VIP (100 nM) desensitization at all frequencies. Relaxations to graded low mechanical distension (1 g) were insensitive to tetrodotoxin (TTX: 1 μM) and L‐NOARG (300 μM), while those to higher distensions (2 g) were slightly inhibited by both agents to the same extent (∼25%). In the human gastric fundus, NOS‐ and VIP immunoreactivities are colocalized in the majority of myenteric neurones. NO and VIP mediate electrically evoked relaxations: low frequency stimulation, irrespective of the duration, caused NO release only, whereas shortlasting stimulation at high frequencies induced NO and VIP release. Relaxations to graded mechanical distension were mostly due to passive viscoelastic properties, with a slight NO‐mediated neurogenic component at 2 g distension. The difference between NO and VIP release suggests that in human fundus accommodation is initiated by NO.

The pharmacological treatment of acute colonic pseudo‐obstruction

Acute colonic pseudo‐obstruction (Ogilvie’s syndrome) can be defined as a clinical condition with symptoms, signs and radiological appearance of acute large bowel obstruction unrelated to any mechanical cause. Recent reports of the efficacy of cholinesterase inhibitors in relieving acute colonic pseudo‐obstruction have fuelled interest in the pharmacological treatment of this condition. The aim of the present review is to outline current perspectives in the pharmacological treatment of patients with acute colonic pseudo‐obstruction.

Primary Enteric Neuropathies Underlying Gastrointestinal Motor Dysfunction

Gastrointestinal functions are controlled by a neural network composed of a multitude of intramural neural elements that constitute the enteric nervous system (ENS) (1–7). The ENS encompasses diverse functionally distinct subclasses of enteric neurons, including primary intrinsic afferent neurons, ascending and descending interneurons, excitatory and inhibitory motor neurons, vasomotor neurons, and secretomotor neurons, which are functionally linked in neural circuitries regulating reflexes and peristalsis (1–7). This highly integrated neural system, localized within the wall of the alimentary tract and extending throughout its entire length, is referred to as the ‘brain of the digestive system’ because of its ability to function in the absence of nerve inputs from the central nervous system (1–6). Along with the intrinsic innervation, extrinsic nerve pathways also contribute to the regulatory mechanisms underlying gut functions (1, 2, 4, 6). In addition to exocrine and endocrine secretions, microcirculation, and motility, recent evidence shows that the ENS is also involved in the control of immune mechanisms and inflammatory processes that occur in the digestive system (8). Damage, either congenital or acquired, to the ENS circuitries may cause a wide array of disorders that are rarely fatal but whose clinical severity can markedly compromise the patient’s quality of life. This review is intended to provide coverage of current knowledge on primary enteric neuropathies as a key pathophysiologic mechanism underlying gastrointestinal motor disorders. In addition to neurons, consistent evidence suggests that interstitial cells of Cajal play an important role in the regulation and pathophysiology of intestinal motility. Since coverage of this aspect is beyond the aim of this review, the reader is referred to a recent article (9).

Clinical Findings and Anti-Neuronal Antibodies in Coeliac Disease with Neurological Disorders

Background: Little is known about the clinical and immunological features of coeliac disease patients with neurological disorders. In a large series of adult coeliac disease patients, we investigated the prevalence of neurological disorders and anti-neuronal antibodies, along with the clinical course. Methods: Neurological symptoms were investigated in 160 consecutive patients (120 F, 40 M) with biopsy-proven coeliac disease. Anti-neuronal antibodies to central/enteric nervous systems were investigated in all neurological patients, 20 unaffected ones and 20 controls. Results: Thirteen (8%) patients had neurological disorders, including epilepsy ( n = 3), attention/memory impairment ( n = 3), cerebellar ataxia ( n = 2), peripheral neuropathy ( n = 2), multiple sclerosis ( n = 1), Moyamoya disease ( n = 1) and Steinerts disease ( n = 1). No significant demographic or clinical differences (gastrointestinal or other gluten-related signs) were found between patients with and without neurological involvement. In all but 2 of the 13 cases, the neurological disorder preceded diagnosis of coeliac disease. Neurological symptoms improved or disappeared in 7 patients who started a gluten-free diet within 6 months after neurological onset, and in none of 4 patients who began later. Prevalence of central nervous system antineuronal antibodies was significantly higher in neurological (61%) than in other patients (5%) ( P = 0.0007) or controls (0%) ( P = 0.00001). Conclusions: Coeliac disease can sometimes present in the guise of a neurological disorder, which may greatly improve when a gluten-free diet is started promptly. Therefore, the possible presence of coeliac disease needs to be carefully considered in patients with cerebellar ataxia, epilepsy, attention/memory impairment or peripheral neuropathy.

Serotonergic and non-serotonergic targets in the pharmacotherapy of visceral hypersensitivity

Abstract  Visceral hypersensitivity is considered a key mechanism in the pathogenesis of functional gastrointestinal (GI) disorders. Targeting visceral hypersensitivity seems an attractive approach to the development of drugs for functional GI disorders. This review summarizes current knowledge on targets for the treatment of visceral hypersensitivity, and the status of current and future drug and probiotic treatment development, and the role of pharmacogenomic factors.

Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons.

Background  Mediators released in the mucosal milieu have been suggested to be involved in visceral hypersensitivity and abdominal pain in patients with irritable bowel syndrome (IBS). However, their impact on myenteric neurons remains unsettled.

The β3‐adrenoceptor agonist SR58611A ameliorates experimental colitis in rats

Abstract  β3‐Adrenoceptor agonists protect against experimental gastric ulcers. We investigated the effects of the β3‐adrenoceptor agonist SR58611A on 2,4‐dinitrobenzene sulphonic acid‐induced colitis in rats and analysed the expression of β3‐adrenoceptors in the colonic wall. SR58611A was administered orally (1–10 mg kg−1) for 7 days, starting the day before induction of colitis. Colitis was assessed by macroscopic and histological scores, tissue myeloperoxidase activity, interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6) and tumour necrosis factor‐α (TNF‐α) levels. Reverse transcription‐polymerase chain reaction and immunohistochemical analysis were used to examine the expression of β3‐adrenoceptors. SR58611A significantly reduced the severity of colitis as well as the tissue levels of TNF‐α, IL‐1β and IL‐6. Colitis was associated with a decreased expression of β3‐adrenoceptor mRNA in the mucosal/submucosal layer of distal colon and this reduction was not affected by SR58611A. Immunohistochemical analysis revealed β3‐adrenoceptors within the muscularis externa, in myenteric neurons and nerve fibres and in the submucosa. β3‐Adrenoceptor immunoreactivity was decreased in inflamed tissues compared to controls, particularly in the myenteric plexus; this reduction was counteracted by SR58611A. Amelioration of experimental colitis by the selective β3‐adrenoceptor agonist SR58611A suggests that β3‐adrenoceptors may represent a therapeutic target in gut inflammation.

Adverse cardiovascular events associated with triptans and ergotamines for treatment of migraine: Systematic review of observational studies

Background Apart from the underlying cardiovascular (CV) risk associated with migraine, both triptans and ergotamines can induce vasoconstriction and potentially increase the risk of serious ischemic events. Because of the low frequency of such events in eligible patients, randomized controlled trials are not exhaustive to assess the drug-related CV risk. Observational studies are, therefore, an essential source of information to clarify this matter of concern. Aim The aim of this study was to systematically review the available published observational studies investigating the risk of serious CV events in triptan or ergotamine users, as compared to unexposed migraineur controls. Methods We systematically searched MEDLINE and EMBASE electronic databases for cohort or case-control studies up to December 1, 2013. Studies retrieved from CDSR, DARE and HTA databases of the Cochrane Library were used for snowballing. Studies investigating the risk of any CV outcome in patients with a migraine diagnosis and exposed to triptans or ergotamines were considered for inclusion. Selection of studies, data extraction, and risk of bias assessment were conducted independently by two reviewers. Pooled odds ratios (ORs) with 95% confidence interval (95% CI) were computed using a random-effects model for studies and outcomes judged eligible for quantitative data synthesis. Results From a total of 3370 citations retrieved, after duplicate removal and screening, only four studies met the inclusion criteria (three nested case-control analyses and one retrospective cohort study). These studies investigated the risk of different CV outcomes associated with either the recency or the intensity of exposure to the studied drugs. As for the intensity of use, the pooled OR of serious ischemic events was 2.28 (95% CI 1.18–4.41; I2 = 0%) for ergotamine use (two studies), whereas for triptans (three studies) it was 0.86 (95% CI 0.52–1.43; I2 = 24.5%). Recent use of ergotamines was not significantly associated with any CV outcome (only one available study). Two studies investigated the risk of stroke related to recent triptan use: the first study reported an OR of 0.90 (0.64–1.26), and the second one suggested an increased risk of 2.51 (1.10–5.71). In this case, because of the high degree of heterogeneity, results were not pooled. Conclusions To date, few comparative observational studies have investigated the CV safety of migraine-specific drugs in clinical practice. Evidence gathered here suggests that intense consumption of ergotamines may be associated with an increased risk of serious ischemic complications. As for triptans, available studies do not suggest strong CV safety issues, although no firm conclusions can be drawn. In particular, evidence on stroke risk is conflicting. However, if an increase of the absolute stroke risk in recently exposed patients does actually exist, it must be small. Overall, residual uncontrolled confounding factors reduce the confidence in the risk estimates collected from the included studies. Further investigations are needed to better define the risk for rare but serious CV events related to triptan and ergotamine use for treatment of migraine.